tbuckley/cabot-search huggingface dataset:
A study of senaparib in combination with temozolomide for the treatment of patients with advanced solid tumors and extensive-stage small cell lung cancer.
Authors: Bo Gao, Chia-Chi Lin, Li-Yuan Bai, Wei-Pang Chung, Wan-Chen Kao, Robert Zielinski, Byoung Yong Shim, Min Hee Hong, Sang-We Kim, Chien-Ying Liu, Chih-Yi Hsieh, Sui Xiong Cai, Ye Edward Tian, Lan Liu, Tiantian Niu, Clare Halcro, Baoyue Li, Ning Ma, Congcong Zhang, Xiangna Chen
Journal: Journal of Clinical Oncology (2022)

3102 Background: Senaparib (or IMP4297) is a PARP inhibitor with a novel chemical structure. Preliminary data demonstrate senaparib has significant anti-tumor activity with good tolerability in some patients with advanced solid tumors. DNA damage caused by temozolomide, a non-classic oral alkylating agent, can sensitize tumors to the effects of PARP inhibitors. In a xenograft model, synergistic antitumor effect was observed with the combination of senaparib and temozolomide, supporting this trial (NCT04434482). Methods: This is a phase Ⅰb/Ⅱ dose-escalation and dose-expansion study. Patients with advanced solid tumors were enrolled for dose escalation to evaluate the safety, tolerability using a modified “3+3” design. Low dose temozolomide (20 to 30 mg, once daily, days 1 to 21) in combination with continuous senaparib (40 to 80 mg, once daily, days 1 to 28) of each 28-day cycle was evaluated. Dose expansion will establish anti-tumor activity and safety of the combination in patients with extensive stage small cell lung cancer (ES-SCLC). Results: A total of 14 patients were enrolled for dose escalation as follows: Cohort 1 (1 patient; senaparib 40 mg plus temozolomide 20 mg), Cohort 2 (3 patients; senaparib 60 mg plus temozolomide 20 mg), Cohort 3 (7 patients; senaparib 80 mg plus temozolomide 20 mg), Cohort 4 (3 patients; senaparib 80 mg plus temozolomide 30 mg). One DLT (Grade 4 thrombocytopenia) was observed in Cohorts 3 and 4. The MTD and RP2D were determined as: senaparib 80 mg plus temozolomide 20 mg. Anaemia, neutropenia and thrombocytopenia were the only Grade ≥3 TEAEs occurring in &gt; 1 patient. All AEs were manageable, and no treatment related deaths were reported. The ORR was observed in 3 of 12 (25.0%) evaluable patients, including 2 confirmed PR and 1 unconfirmed PR. The DCR was 83.3% (10 of 12 evaluable patients). Two patients remain on treatment for more than 1 year. Conclusions: Preliminary results suggest that low dose temozolomide (D1-21 of a 28-day cycle) in combination with continuous senaparib is generally well tolerated with encouraging anti-tumor activity. Recruitment for dose expansion for ES-ECLC patients has commenced (Sep 2021). Clinical trial information: NCT04434482.
Impact of immunotherapy best practice alert on physician awareness of immune-related adverse events and patient outcomes in the urgent and emergent care setting.
Authors: Jessica Sassic, Aren Ebrahimi, Kathryn Blount Bollin
Journal: Journal of Clinical Oncology (2022)

e13540 Background: Immune checkpoint inhibitors (ICI) are used to treat a wide range of malignancies and can provoke inflammatory side effects in any organ system. These immune-related adverse events (irAEs) are graded in severity according to the Common Terminology Criteria for Adverse Events (CTCAE) which serves as the basis for strategic toxicity management. Cancer patients treated with ICIs often present to urgent care (UC) and emergency room (ER) settings for CTCAE grade 2-4 irAEs. Providers in these settings need to recognize these irAEs as the treatment differs from chemotherapy toxicity management. Best practice alerts (BPAs) have been integrated in the electronic health record (EHR) to raise provider awareness to patients’ unique risk factors and improve patient outcomes. For example, a BPA for patients prescribed second generation antipsychotics led to more in-hospital providers ordering the appropriate laboratory studies to screen for metabolic derangements. Here, we describe our retrospective institutional protocol for the assessment of provider awareness and patient outcomes prior to and after the implementation of a BPA for patients receiving ICIs and presenting to an UC or ER with symptoms attributable to irAEs. Methods: Our institution will implement a BPA that identifies patients treated with ICIs within 6 months of presentation to an institutional UC or ER. The BPA will require providers to check a yes/no box asking if they considered an irAE in the differential diagnosis for the patient’s presenting symptom prior to advancing in the EHR. The BPA will include a hyperlink to the current American Society of Clinical Oncology guidelines for management of irAEs. After BPA implementation we will retrospectively analyze the EHR of patients treated with ICIs who presented to an institutional UC or ER for the time periods of 6-months prior to and after the implementation of the BPA. Our analysis will include review of the UC/ER providers’ differential diagnoses, imaging and laboratory studies, subspecialty consultations, and treatments provided. Our primary endpoint will be the quantification of patients diagnosed with an irAE at presentation both prior to and after implementation of the BPA. The secondary endpoints will include quantification of patients who received guideline-based management of irAEs in the UC/ER setting, time to resolution of symptoms to CTCAE grade 1 or less, and analysis of subspecialist involvement in the management of an identified irAE. We plan to use the Chi-squared method to observe for statistical significance of endpoints between the pre- and post- periods of BPA implementation. Our aim is to demonstrate the utility of a BPA in promoting the appropriate assessment and management of irAEs in cancer patients receiving checkpoint immunotherapies.
Principles of Management of Patients With Ampullary Adenocarcinoma
Authors: Stephen W. Behrman
Journal: Journal of the National Comprehensive Cancer Network (2022)

Ampullary adenocarcinoma is an uncommon neoplasm that most often requires pancreatoduodenectomy, has a less than optimal cure rate, and is a cancer for which the impact of multidisciplinary care remains unclear. Although often believed to have a better prognosis than pancreatic cancer, ampullary cancer remains a highly lethal disease. Given its rarity and the typical lack of surrounding vessel invasion, a surgery-first approach has most commonly been used in treatment sequencing. The literature has yielded conflicting results regarding the use of adjuvant therapy. Neoadjuvant therapy has received little attention but offers promise with regard to pathologic downstaging, particularly when chemotherapy is combined with radiation. Genetic evaluation may help guide future therapies, and multi-institutional trials are needed to develop optimal treatment sequencing and directed at the 2 specific histologic subtypes.
Consequences of the COVID-19 pandemic on new cancer visits to a comprehensive cancer center in New York.
Authors: Katherine Garcia, Abhinav Rohatgi, Chinyere Okpara, Megan Winner, Jeffrey S. Weber, Marc Justin Braunstein
Journal: Journal of Clinical Oncology (2022)

e18752 Background: Studies on cancer patients during the COVID-19 pandemic have shown a decrease in new diagnoses, delays in care, and a shift to later stage disease presentations. Considering that NY has been an epicenter for COVID-19 in the U.S., we investigated its impact on new cancer diagnoses at the two campuses of NYU’s Perlmutter Cancer Center and hypothesized that there would be a decrease in presentations during the peak outbreaks in NY. Methods: We conducted a single center, retrospective analysis of new cancer diagnoses before, during, and after the peak of the pandemic between Dec 1, 2019, and Aug 31, 2020. Following IRB approval, subjects were identified using our cancer center database, which includes both inpatient and outpatient visits. Subjects were included regardless of their treatment plan. New diagnoses before COVID-19 (Dec to Feb), at first peak (March to May), and during the initial recovery phase (June-Aug) were assessed. No COVID-19 vaccines were available during this time. Results: As summarized in Table, during the initial COVID-19 peak, there was a substantial decrease in new patient visits with statistically significant differences seen by age and certain cancer types including breast, skin, and hematologic malignancies. In all cancers, there was a decrease in the proportion of new patient visits among those over age 75 during the peak. When confining analyses to breast, skin, and hematologic cancers, we saw a significant increase in the proportion of younger new patients at the peak period. We also observed an association between age and stage, with an increase in new stage I diagnoses in the younger (age 18-54) population at peak. Telemedicine was most utilized by the younger population during both peak and recovery periods. Conclusions: In this retrospective analysis, we found that during the initial COVID-19 peak, prior to vaccine availability, outpatient visits for hematologic and solid malignancies decreased at our cancer center in NY. The decrease in the proportion of all cancer types in elderly patients during the peak was likely related to hesitancy among this vulnerable population to seek care. The widespread use of telemedicine also likely contributed to the increased incidence in new patient visits in younger patients. Lessons learned from this experience can help guide outreach to vulnerable populations during future outbreaks, particularly by fostering telemedicine use among the elderly.[Table: see text]
Educational impact of inpatient hematology-oncology service structure.
Authors: Jennifer H. Cooperrider, Anand Ashwin Patel, Sam Brondfield
Journal: Journal of Clinical Oncology (2022)

e23013 Background: Literature suggests that inpatient hematology-oncology (heme-onc) clinical experiences may have a deleterious impact on trainee interest in heme-onc. However, the impact of inpatient heme-onc service structure on trainee education is not known. To delineate the factors affecting trainee education, we aimed to characterize the structure of inpatient heme-onc services at comprehensive cancer centers (CCCs) and the associated impact on trainees. Methods: We designed a survey with Likert-type and open-ended questions using established procedures. We surveyed heme-onc fellowship program directors (PDs) at all 50 U.S. CCCs with fellowship programs. We performed point biserial and Pearson correlations on Likert-type responses and content analysis on open-ended responses. Results: Eighteen out of 50 (36%) PDs responded and described 117 services. Services were either primary (35%), consult (44%), or both (21%). Fellows were present on 93% and residents on 54% of services. PDs rated the educational value of most inpatient services as either “very high” or “somewhat high” for both fellows (73% very high, 13% somewhat high) and residents (49% very high, 33% somewhat high). PDs perceived that fellows derived greater educational value from consult-only vs primary/mixed services [R(105) = 0.25, p= 0.01] and provided greater reciprocal benefit to consult-only vs primary/mixed services [R(100) = 0.28, p= 0.004]. Hospital type (county, university, or veteran’s) and the presence or absence of a formal curriculum on the service did not correlate with perceived educational benefit. Multiple open-ended comments suggested that heme-onc attendings and fellows should be consultative rather than primary service providers, programs should separate teaching and non-teaching services, and service/education balance optimization should be prioritized. Inadequate service staffing and lack of institutional support were identified as barriers to inpatient education. Conclusions: PDs felt that inpatient heme-onc services had high educational value for trainees, particularly for fellows. Both fellows and services may derive mutual benefit from fellow participation on inpatient consult services structured separately from non-teaching primary services. Hospital type and the presence or absence of a structured curriculum may not be critical for education on inpatient heme-onc services. Appropriate service/education balance, staffing, and institutional support are crucial to optimize inpatient education. Future studies should explore the trainee perspective around the educational value of inpatient clinical experiences. PDs and institutions can use the study findings to craft beneficial inpatient educational experiences for heme-onc trainees.
Exercise-induced right ventricular alterations in a rodent model of athletes heart
Authors: A Olah, B Bodi, AA Sayour, BA Barta, M Ruppert, O Bottlik, B Merkely, Z Papp, T Radovits
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00837/21) to AO National Research, Development and Innovation Office (NKFIH) of Hungary (K120277 and K135076 to BM) Background Intense sports activity leads to the adaptation of cardiac structure and function, the so-called athlete’s heart. Research over the last years has focused on exercise-induced adaptation of the right ventricle (RV), because the disproportionate load on the RV - when compared with left ventricle - might lead to pathological consequences, such as interstital fibrosis or chamber dilation. Purpose We aimed at investigating right ventricular alterations induced by regular aerobic exercise training in a rat model of athlete's heart. Methods Young, adult rats were divided into control (Co) and exercised (Ex) groups. Trained rats swam 200 min/day for 12 weeks. In vivo electrophysiological study and in vitro force measurements on isolated permeabilized cardiomyocytes were carried out to investigate electrical and functional alterations, respectively. Molecular biological (qRT-PCR, Western-blot) and histological investigations were applied to reveal underlying mechanisms. Results Exercise training was associated with increased RV cardiomyocyte width (12.5±0.1µm Co vs. 13.8±0.2µm Ex, p&amp;lt;0.05) and corresponding hyperphosphorylation of protein kinase B (Akt). RV myofilaments from exercised animals showed increased maximal force development and improved calcium sensitivity. Sarcomere protein investigations revealed marked overall and site-specific hypophosphorylation of troponin I. We found prolonged QT interval and right ventricular effective refracter period (RVERP: 44.0±1.6ms Co vs. 52.8±2.1ms Ex, p&amp;lt;0.05) along with decreased gene expression of potassium channels. Picrosirius staining did not reveal fibrosis, that was underlied by unchanged protein expression of connective tissue growth factor (CTGF) and gene expression of profibrotic markers. Gene expression of apoptotic markers and fetal gene program did not differ between the groups. Conclusions According to our data, regular swim training induced RV hypertrophy, that was associated with functional improvement adn hypophosphorilation of troponin I. Prolonged repolarization without pathological alterations in RV myocardial tissue suggest physiological remodeling after balanced training.
Lnc-EST12, which is negatively regulated by mycobacterial EST12, suppresses antimycobacterial innate immunity through its interaction with FUBP3
Authors: Qili Yao, Yan Xie, Dandan Xu, Zilu Qu, Jian Wu, Yuanyuan Zhou, Yuying Wei, Huan Xiong, Xiao-Lian Zhang
Journal: Cellular and Molecular Immunology (2022)
Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in combination with MEK inhibition in preclinical models of human NRAS mutant melanoma.
Authors: Nichol Miller, Tim Sen Wang, Catherine Lee, Paul Severson, Eugene Ke, Ken Kobayashi, Richard Thomas Williams
Journal: Journal of Clinical Oncology (2022)

e15099 Background: NRAS mutations which activate MAPK signaling represent oncogenic driver alterations in approximately 20% melanoma cases in the US. NRAS mutant melanomas are uniquely dependent upon CRAF rather than BRAF for activation of downstream MEK/ERK signaling. In BRAF mutant melanoma, approved RAF-targeted therapies are commonly used in combination with a MEK inhibitor which provides clinical benefit by inhibition of two targets within the oncogenic MAPK signaling pathway. Emerging data with pan-RAF inhibitors in early clinical development suggests benefit with and without combined MEK inhibition, yet no approved targeted therapy exists for NRAS mutant melanoma patients. KIN-2787 is a novel, orally available pan-RAF inhibitor designed to be effective in RAF-dependent cancers, regardless of isoform. Methods: Kinome profiling was evaluated by radiometric enzyme assay at Reaction Biology across 688 kinases (including wild type, atypical, and mutant). Cellular activity was assessed by suppression of downstream MAPK pathway signaling and cell growth inhibition in human tumor cell lines. Combination cell growth inhibition studies were performed in 9x5 dose matrices with KIN-2787 and binimetinib, respectively. Extended cell growth inhibition effects were assessed by Incucyte imaging. In vivo KIN-2787 and combination efficacy was evaluated in NRAS mutant xenograft models. Results: Kinome profiling of KIN-2787 revealed exquisite selectivity with only 2 of 669 non-RAF family kinases inhibited &gt; 75% at 1 M KIN-2787 and retained ̃10x and 70x selectivity window against those two kinases, DDR1 and p38b, respectively, relative to RAF kinases. We previously reported KIN-2787 activity across BRAF, NRAS, and KRAS mutant tumor cell lines with greatest sensitivity in Class II and III dimer-driven BRAF models. Here, we evaluated NRAS mutant, BRAF WT melanoma for combination potential with binimetinib. Melanoma tumor cell lines bearing NRAS hotspot mutations demonstrated synergistic benefit with KIN-2787 combined with binimetinib. Daily KIN-2787 plus binimetinib treatment in NRAS mutant melanoma xenograft models resulted in significant tumor growth inhibition benefit relative to either agent alone and was associated with added MAPK pathway biomarker suppression. Conclusions: KIN-2787 is a highly selective, potent, next-generation, pan-RAF inhibitor with activity across BRAF and RAS mutant human tumor cell models. Preclinical in vitro and in vivo studies using KIN-2787 in combination with binimetinib demonstrated significant combination benefit in NRAS mutant melanoma models. Taken together with its unique selectively, these data support use of KIN-2787 in combination therapy in this patient segment. A Phase 1/1b dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is ongoing (NCT04913285).
QOL-23. Expanded protocols for hearing loss related cisplatin-based therapy in childhood cancer patients.
Authors: Amy Grosnik, Richard T Graham, Natasha Pillay-Smiley, Peter de Blank, Trent Hummel, Aaron Mochizuki, Scott Raskin, Ian Windmill
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Most children who require cisplatin chemotherapy incur hearing loss. The basal end of the cochlea, corresponding to high frequency sound perception, is typically affected first, with progression along the basilar membrane and to lower frequencies over time. Typical audiologic protocols for children are often restricted to the speech frequencies (500-4000Hz). However, reliable responses to higher frequencies can be obtained using specialized electrophysiologic measures or adapted behavioral test procedures, which may lead to earlier identification of hearing loss during ototoxicity monitoring. METHODS: Auditory Brainstem Response (ABR) and behavioral threshold assessments were completed for patients during cisplatin treatment at Cincinnati Children’s Hospital between 2017 and 2021. High frequency ABR protocols were established to include 6000 and 8000 Hz and behavioral testing protocols were expanded to include frequencies 8000 through 16000 Hz. Hearing loss was defined as &amp;gt;20 dB eHL at any frequency. The typical and high frequency protocols were compared to determine if higher frequency measurement provides a more sensitive means to detect the onset of hearing loss. RESULTS: One-hundred and fifty-three patients receiving cisplatin were assessed audiometrically. For patients who required ABR evaluations, 38% were identified with hearing loss when using the typical test protocol, where 79% of the patients were identified with hearing loss when using the high frequency protocol. For patients who were able to complete behavioral audiometric evaluations, 42% were identified with hearing loss with the typical protocol while 84% were identified with the high frequency protocol. CONCLUSIONS: The addition of higher frequencies to audiologic evaluation protocols for both ABR and behavioral audiometry significantly increases sensitivity to detect hearing loss during ototoxicity monitoring of cisplatin treatment and is a feasible strategy in pediatric cancer patients. Audiologically, the increased sensitivity to detect hearing loss may lead to earlier intervention regarding hearing and communication for the patient/family.
The awareness of thromboembolic risk amongst Klinefelter Syndrome (47, XXY) patients- a clot in the knowledge?
Authors: S. Birch, F. Melling, Y. Kailash, P. Carroll, A. El-Shirif, L. Frodsham, M. Sallman, P. Allchorne, T. Yap
Journal: European Urology (2022)
Validation of the <i>PREDICT </i>breast cancer tool in a multiethnic population of U.S. women after a second primary breast cancer.
Authors: Zhengyi Deng, Miranda R Jones, Mei-Cheng Wang, Kala Visvanathan
Journal: Journal of Clinical Oncology (2022)

10551 Background: PREDICT is a widely used clinical tool to estimate prognosis based on treatment after a diagnosis of early-stage breast cancer (BC). However, it has not been validated for use in women diagnosed with a second primary BC. Methods: Women diagnosed with one or two BCs between 2000-2013 were identified from the US Surveillance, Epidemiology, and End Results (SEER) program. Validation analyses were conducted separately among women with one and two BCs. For each group, absolute and relative differences in predicted (P) and observed (O) 5-year BC-specific mortality were estimated stratified by estrogen receptor (ER) status. For women with two BCs, mortality prediction was based on demographic and tumor characteristics of their second BCs. Model discrimination was evaluated by receiver-operator curve (ROC) and area under the curve (AUC). Results: 6,729 women diagnosed with a second BC and 357,204 women with only one BC were included. Among women with one ER-positive BC, the predicted (P) and observed (O) BC mortality were comparable [absolute difference (P-O): -0.22%, 95%CI: -0.29%, -0.15%]. For women diagnosed with a second ER-positive disease, the model largely underestimated the BC mortality (P-O: -6.24%, 95%CI: -6.96%, -5.49%). An underestimation of 3%-15% in absolute BC mortality was observed in subgroup analyses based on age, race/ethnicity [P-O for Non-Hispanic (NH) White, NH Black, and Hispanic were -5.63%, -9,3%, and -9.24%], chemotherapy (P-O: -9.06, 95%CI: -10.79, -7.4), radiation therapy (P-O: -5.06, 95%CI: -6.29, -3.93) and tumor characteristics. PREDICT overestimated BC mortality for women diagnosed with one ER-negative BC (P-O: 4.54%, 95%CI: 4.27%, 4.86%) but it performed well for women diagnosed with a second ER-negative BC (P-O: -1.69%, -3.99%, 0.16%). However, in subgroup analyses among women with two BCs the tool underestimated mortality for women with a second ER-negative disease if their first cancer was diagnosed before age 50 years (P-O: -3.27, 95%CI: -6.48, -0.06), was poorly differentiated (P-O: -4.08, 95%CI: -7.09, -1.2), or ER-negative (P-O: -4.68, 95%CI: -7.62, -1.39). The overall AUCs for first and second ER-positive and ER-negative BCs ranged between 0.73 and 0.82. Conclusions: The PREDICT tool largely underestimated the 5-year BC-specific mortality in women diagnosed with a second ER-positive breast cancer and in many subgroups of women diagnosed with a second ER-negative cancer. Novel prognostic tools are needed for women diagnosed with a second breast cancer.